Regulation of vascular smooth muscle cell plasticity

血管平滑肌细胞可塑性的调节

• 批准号: 9211370
• 负责人: Kathleen Ann Martin
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-03 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211370
• 关键词: Angioplasty; Atherosclerosis; Biology; Blood Vessels; Blood flow; Bypass; Cardiovascular system; Cell Cycle; Cell Differentiation process; Cellular biology; Chromatin; Complement; DNA; DNA Methylation; Data; Embryo; Epigenetic Process; Failure; Family; Future; Gene Expression; Genes; Goals; Growth; Growth Factor; Hematopoietic stem cells; Hyperplasia; In Vitro; Individual; Injury; Knock-out; Knockout Mice; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Conformation; Muscle Cells; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Phenotype; Platelet-Derived Growth Factor; Prevention therapy; Procedures; Process; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Role; Sampling; Sirolimus; Smooth Muscle; Stem Cell Factor; Stem cells; Stents; Surgical complication; Testing; Therapeutic; Transplantation; Vascular Diseases; Vascular Smooth Muscle; Viral; c-myc Genes; cardiovascular disorder therapy; cell dedifferentiation; femoral artery; graft failure; healing; improved; in vivo; in vivo Model; inhibitor/antagonist; knock-down; myocardin; novel; overexpression; pluripotency; programs; promoter; public health relevance; response; restenosis

DESCRIPTION (provided by applicant): Regulation of VSMC phenotype remains a key unanswered question in vascular smooth muscle cell (VSMC) biology. VSMC retain a remarkable plasticity to de-differentiate and re-enter the cell cycle allowing for growth and healing. However, such plasticity can also contribute to severe vascular pathologies, including restenosis, graft failure, atherosclerosis, and transplant vasculopathy. Remarkably, despite intense study, the process regulating VSMC plasticity is largely unknown with few therapies successfully targeting this process. With the growing numbers of patients suffering from vascular disease the discovery of novel targets is urgently warranted. We have made the exciting discovery that de-differentiated VSMC express genes associated with stem cell pluripotency, including Sox2, Oct4, Nanog, and KLF4. We propose that these stem cell-associated genes account for the unique plasticity of mature VSMC. Recent groundbreaking studies have identified the TET (ten-eleven translocations) family of chromatin modifying proteins as key mediators of pluripotency in embryonic and hematopoietic stem cells. Our Preliminary Results implicate TET2 as an epigenetic master regulator of VSMC phenotype. Importantly, we find that TET2 inhibits expression of stem cell-associated genes and classic markers of the de-differentiated phenotype. We previously discovered that the mTORC1 inhibitor, rapamycin, promotes VSMC differentiation. We now find that rapamycin regulates TET2 expression. Remarkably, we find that TET2 also regulates miRNAs that can modulate both differentiation-specific and stem cell-associated gene expression. We hypothesize that TET2 is a master regulator of VSMC phenotype through its coordinated regulation of the promoters of contractile and stem cell-associated genes, as well as of miRNAs. In Specific Aim 1, we will determine the role of stem cell-associated genes in VSMC phenotype. In Specific Aim 2, we will determine the role of TET2-regulated miRNAs in VSMC phenotype. In Specific Aim 3, we will determine whether targeting TET2 or stem cell-associated genes has therapeutic utility in in vivo models of intimal hyperplasia. If our goals are achieved, we will have identified a nove mechanism underlying VSMC plasticity. Understanding the critical mechanisms by which mTORC1 regulates VSMC phenotype will lead to improved cardiovascular therapeutics.

描述（由申请人提供）：血管平滑肌细胞表型的调控仍然是血管平滑肌细胞（VSMC）生物学中一个悬而未决的关键问题。VSMC保留了一个显著的可塑性去分化和重新进入细胞周期允许生长和愈合。然而，这种可塑性也可能导致严重的血管病变，包括再狭窄、移植物衰竭、动脉粥样硬化和移植血管病变。值得注意的是，尽管有大量的研究，调节VSMC可塑性的过程在很大程度上是未知的，很少有治疗方法成功地针对这一过程。随着血管疾病患者数量的不断增加，迫切需要发现新的靶点。我们已经取得了令人兴奋的发现，去分化的VSMC表达与干细胞多能性相关的基因，包括Sox2， Oct4， Nanog和KLF4。我们认为这些干细胞相关基因解释了成熟VSMC独特的可塑性。最近的突破性研究已经确定了TET（10 - 11易位）家族染色质修饰蛋白是胚胎和造血干细胞多能性的关键介质。我们的初步结果表明TET2是VSMC表型的表观遗传主控因子。重要的是，我们发现TET2抑制干细胞相关基因和去分化表型的经典标记的表达。我们之前发现mTORC1抑制剂雷帕霉素促进VSMC分化。我们现在发现雷帕霉素调节TET2的表达。值得注意的是，我们发现TET2也调节可以调节分化特异性和干细胞相关基因表达的mirna。我们假设TET2通过协调调节收缩基因和干细胞相关基因的启动子以及mirna，是VSMC表型的主要调节剂。在特异性目标1中，我们将确定干细胞相关基因在VSMC表型中的作用。在Specific Aim 2中，我们将确定tet2调控的mirna在VSMC表型中的作用。在Specific Aim 3中，我们将确定TET2或干细胞相关基因在体内内膜增生模型中是否具有治疗效用。如果我们的目标实现了，我们将确定一个潜在的VSMC可塑性机制。了解mTORC1调节VSMC表型的关键机制将有助于改善心血管治疗。